The Hypocretin/Orexin System: An Increasingly Important Role in Neuropsychiatry

Medicinal Research Reviews

Volumn 35, Issue 1, 2015, Pages 152-197

  Chen, Quanhui ^a,b   de Lecea, Luis ^c   Hu, Zhian ^a   Gao, Dong ^b  

^a THIRD MILITARY MEDICAL UNIVERSITY   (China)

^b THIRD MILITARY MEDICAL UNIVERSITY   (China)

^c STANFORD UNIVERSITY   (United States)

Author keywords

Addiction; Arousal; Hypocretin; Neuropsychiatry; Orexin

Indexed keywords

1 (2 METHYL 6 BENZOXAZOLYL) 3 (1,5 NAPHTHYRIDIN 4 YL)UREA; ALMOREXANT; OREXIN; OREXIN RECEPTOR; SB 649868; NEUROPEPTIDE; OREXINS; SIGNAL PEPTIDE;

ADDICTION; ANXIETY; APPETITE; AROUSAL; ARTICLE; BRAIN NERVE CELL; BRAIN REGION; CELL TRANSPLANTATION; COGNITION; DEGENERATIVE DISEASE; DEPRESSION; EATING DISORDER; GENE TARGETING; HUMAN; LATERAL HYPOTHALAMUS; NARCOLEPSY; NEUROPATHOLOGY; NEUROPHYSIOLOGY; NEUROPSYCHIATRY; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POSTTRAUMATIC STRESS DISORDER; RANDOMIZED CONTROLLED TRIAL (TOPIC); REWARD; SCHIZOPHRENIA; SIGNAL TRANSDUCTION; SLEEP DISORDER; STRESS; PHYSIOLOGY;

HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; NEUROPEPTIDES; NEUROPSYCHIATRY;

EID: 84915782607     PISSN: 01986325     EISSN: 10981128     Source Type: Journal    
DOI: 10.1002/med.21326     Document Type: Article

References (375)

1. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS, 2nd, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG. The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 1998;95(1):322-327.
2. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richarson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M. Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998;92(4):573-585.
3. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999;98(3):365-376.
4. Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 1998;18(23):9996-10015.
5. Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM. Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 1998;438(1-2):71-75.
6. Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 2001;435(1):6-25.
7. Hagan JJ, Leslie RA, Patel S, Evans ML, Wattam TA, Holmes S, Benham CD, Taylor SG, Routledge C, Hemmati P, Munton RP, Ashmeade TE, Shah AS, Hatcher JP, Hatcher PD, Jones DN, Smith MI, Piper DC, Hunter AJ, Porter RA, Upton N. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci USA 1999;96(19):10911-10916.
8. Lambe EK, Olausson P, Horst NK, Taylor JR, Aghajanian GK. Hypocretin and nicotine excite the same thalamocortical synapses in prefrontal cortex: Correlation with improved attention in rat. J Neurosci 2005;25(21):5225-5229.
9. Haynes AC, Jackson B, Chapman H, Tadayyon M, Johns A, Porter RA, Arch JR. A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul Pept 2000;96(1-2):45-51.
10. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M. Narcolepsy in orexin knockout mice: Molecular genetics of sleep regulation. Cell 1999;98(4):437-451.
11. Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, Nevsimalova S, Aldrich M, Reynolds D, Albin R, Li R, Hungs M, Pedrazzoli M, Padigaru M, Kucherlapati M, Fan J, Maki R, Lammers GJ, Bouras C, Kucherlapati R, Nishino S, Mignot E. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000;6(9):991-997.
12. Uslaner JM, Tye SJ, Eddins DM, Wang X, Fox SV, Savitz AT, Binns J, Cannon CE, Garson SL, Yao L, Hodgson R, Stevens J, Bowlby MR, Tannenbaum PL, Brunner J, McDonald TP, Gotter AL, Kuduk SD, Coleman PJ, Winrow CJ, Renger JJ. Orexin receptor antagonists differ from standard sleep drugs by promoting sleep at doses that do not disrupt cognition. Sci Transl Med 2013;5(179):179ra144.
13. Tsunematsu T, Yamanaka A. The role of orexin/hypocretin in the central nervous system and peripheral tissues. Vitam Horm 2012;89:19-33.
14. Tsujino N, Sakurai T. Orexin/hypocretin: A neuropeptide at the interface of sleep, energy homeostasis, and reward system. Pharmacol Rev 2009;61(2):162-176.
15. Kukkonen JP. Physiology of the orexinergic/hypocretinergic system: a revisit in 2012. Am J Physiol Cell Physiol 2013;304(1):C2-32.
16. Sakurai T. The neural circuit of orexin (hypocretin): Maintaining sleep and wakefulness. Nat Rev Neurosci 2007;8(3):171-181.
17. Gotter AL, Webber AL, Coleman PJ, Renger JJ, Winrow CJ. International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin receptor function, nomenclature and pharmacology. Pharmacol Rev 2012;64(3):389-420.
18. Li J, Hu Z, de Lecea L. The hypocretins/orexins: Integrators of multiple physiological functions. Br J Pharmacol 2014;171(2):332-350.
19. Torrealba F, Yanagisawa M, Saper CB. Colocalization of orexin a and glutamate immunoreactivity in axon terminals in the tuberomammillary nucleus in rats. Neuroscience 2003;119(4):1033-1044.
20. Borgland SL, Storm E, Bonci A. Orexin B/hypocretin 2 increases glutamatergic transmission to ventral tegmental area neurons. Eur J Neurosci 2008;28(8):1545-1556.
21. Chou TC, Lee CE, Lu J, Elmquist JK, Hara J, Willie JT, Beuckmann CT, Chemelli RM, Sakurai T, Yanagisawa M, Saper CB, Scammell TE. Orexin (hypocretin) neurons contain dynorphin. J Neurosci 2001;21(19):RC168 (1-6).
22. Eriksson KS, Sergeeva OA, Selbach O, Haas HL. Orexin (hypocretin)/dynorphin neurons control GABAergic inputs to tuberomammillary neurons. Eur J Neurosci 2004;19(5):1278-1284.
23. Holmqvist T, Akerman KE, Kukkonen JP. Orexin signaling in recombinant neuron-like cells. FEBS Lett 2002;526(1-3):11-14.
24. Soffin EM, Gill CH, Brough SJ, Jerman JC, Davies CH. Pharmacological characterisation of the orexin receptor subtype mediating postsynaptic excitation in the rat dorsal raphe nucleus. Neuropharmacology 2004;46(8):1168-1176.
25. 2+ signalling by the orexin receptor type 1. Biochem Pharmacol 2006;71(6):827-836.
26. Holmqvist T, Johansson L, Ostman M, Ammoun S, Akerman KE, Kukkonen JP. OX1 orexin receptors couple to adenylyl cyclase regulation via multiple mechanisms. J Biol Chem 2005;280(8):6570-6579.
27. Tang J, Chen J, Ramanjaneya M, Punn A, Conner AC, Randeva HS. The signalling profile of recombinant human orexin-2 receptor. Cell Signal 2008;20(9):1651-1661.
28. Bernard R, Lydic R, Baghdoyan HA. Hypocretin-1 causes G protein activation and increases ACh release in rat pons. Eur J Neurosci 2003;18(7):1775-1785.
29. Bernard R, Lydic R, Baghdoyan HA. Hypocretin-1 activates G proteins in arousal-related brainstem nuclei of rat. Neuroreport 2002;13(4):447-450.
30. van den Pol AN, Gao XB, Obrietan K, Kilduff TS, Belousov AB. Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin. J Neurosci 1998;18(19):7962-7971.
31. Yang B, Samson WK, Ferguson AV. Excitatory effects of orexin-A on nucleus tractus solitarius neurons are mediated by phospholipase C and protein kinase C. J Neurosci 2003;23(15):6215-6222.
32. Zhu Y, Miwa Y, Yamanaka A, Yada T, Shibahara M, Abe Y, Sakurai T, Goto K. Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussis toxin-sensitive and -insensitive G-proteins. J Pharmacol Sci 2003;92(3):259-266.
33. 2+ signaling in a reciprocal manner to leptin: Orexigenic neuronal pathways in the mediobasal hypothalamus. Eur J Neurosci 2004;19(6):1524-1534.
34. van den Top M, Nolan MF, Lee K, Richardson PJ, Buijs RM, Davies CH, Spanswick D. Orexins induce increased excitability and synchronisation of rat sympathetic preganglionic neurones. J Physiol 2003;549(Pt 3):809-821.
35. Lopez M, Senaris R, Gallego R, Garcia-Caballero T, Lago F, Seoane L, Casanueva F, Dieguez C. Orexin receptors are expressed in the adrenal medulla of the rat. Endocrinology 1999;140(12):5991-5994.
36. Randeva HS, Karteris E, Grammatopoulos D, Hillhouse EW. Expression of orexin-A and functional orexin type 2 receptors in the human adult adrenals: Implications for adrenal function and energy homeostasis. J Clin Endocrinol Metab 2001;86(10):4808-4813.
37. 2+ signaling in dopamine neurons of the ventral tegmental area. Neuroreport 2001;12(9):1885-1889.
38. Xu R, Roh SG, Gong C, Hernandez M, Ueta Y, Chen C. Orexin-B augments voltage-gated L-type Ca(2+) current via protein kinase C-mediated signalling pathway in ovine somatotropes. Neuroendocrinology 2003;77(3):141-152.
39. Li B, Chen F, Ye J, Chen X, Yan J, Li Y, Xiong Y, Zhou Z, Xia J, Hu Z. The modulation of orexin A on HCN currents of pyramidal neurons in mouse prelimbic cortex. Cereb Cortex 2010;20(7):1756-1767.
40. Kawada Y, Ueno S, Asayama K, Tsutsui M, Utsunomiya K, Toyohira Y, Morisada N, Tanaka K, Shirahata A, Yanagihara N. Stimulation of catecholamine synthesis by orexin-A in bovine adrenal medullary cells through orexin receptor 1. Biochem Pharmacol 2003;66(1):141-147.
41. Smart D, Jerman JC, Brough SJ, Rushton SL, Murdock PR, Jewitt F, Elshourbagy NA, Ellis CE, Middlemiss DN, Brown F. Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR. Br J Pharmacol 1999;128(1):1-3.
42. Lund PE, Shariatmadari R, Uustare A, Detheux M, Parmentier M, Kukkonen JP, Akerman KE. The orexin OX1 receptor activates a novel Ca2+ influx pathway necessary for coupling to phospholipase C. J Biol Chem 2000;275(40):30806-30812.
43. 2+ influx. Br J Pharmacol 2007;150(1):97-104.
44. 2+ channels. Neuroreport 2001;12(9):2017-2020.
45. 2+ influx in OX1 receptor signaling. Mol Endocrinol 2006;20(1):80-99.
46. Peltonen HM, Akerman KE, Bart G. A role for PKD1 and PKD3 activation in modulation of calcium oscillations induced by orexin receptor 1 stimulation. Biochim Biophys Acta 2010;1803(10):1206-1212.
47. Van Lint J, Rykx A, Maeda Y, Vantus T, Sturany S, Malhotra V, Vandenheede JR, Seufferlein T. Protein kinase D: An intracellular traffic regulator on the move. Trends Cell Biol 2002;12(4):193-200.
48. Rozengurt E, Rey O, Waldron RT. Protein kinase D signaling. J Biol Chem 2005;280(14):13205-13208.
49. Gorojankina T, Grebert D, Salesse R, Tanfin Z, Caillol M. Study of orexins signal transduction pathways in rat olfactory mucosa and in olfactory sensory neurons-derived cell line Odora: Multiple orexin signalling pathways. Regul Pept 2007;141(1-3):73-85.
50. Nakamura Y, Miura S, Yoshida T, Kim J, Sasaki K. Cytosolic calcium elevation induced by orexin/hypocretin in granule cell domain cells of the rat cochlear nucleus in vitro. Peptides 2010;31(8):1579-1588.
51. Malendowicz LK, Tortorella C, Nussdorfer GG. Orexins stimulate corticosterone secretion of rat adrenocortical cells, through the activation of the adenylate cyclase-dependent signaling cascade. J Steroid Biochem Mol Biol 1999;70(4-6):185-188.
52. Nanmoku T, Isobe K, Sakurai T, Yamanaka A, Takekoshi K, Kawakami Y, Ishii K, Goto K, Nakai T. Orexins suppress catecholamine synthesis and secretion in cultured PC12 cells. Biochem Biophys Res Commun 2000;274(2):310-315.
53. Mazzocchi G, Malendowicz LK, Gottardo L, Aragona F, Nussdorfer GG. Orexin A stimulates cortisol secretion from human adrenocortical cells through activation of the adenylate cyclase-dependent signaling cascade. J Clin Endocrinol Metab 2001;86(2):778-782.
54. Shin HS, Cho HS, Sung KW, Yoon BJ. Orexin-A increases cell surface expression of AMPA receptors in the striatum. Biochem Biophys Res Commun 2009;378(3):409-413.
55. Selbach O, Bohla C, Barbara A, Doreulee N, Eriksson KS, Sergeeva OA, Haas HL. Orexins/hypocretins control bistability of hippocampal long-term synaptic plasticity through co-activation of multiple kinases. Acta Physiol (Oxf) 2010;198(3):277-285.
56. Spinazzi R, Ziolkowska A, Neri G, Nowak M, Rebuffat P, Nussdorfer GG, Andreis PG, Malendowicz LK. Orexins modulate the growth of cultured rat adrenocortical cells, acting through type 1 and type 2 receptors coupled to the MAPK p42/p44- and p38-dependent cascades. Int J Mol Med 2005;15(5):847-852.
57. Ammoun S, Lindholm D, Wootz H, Akerman KE, Kukkonen JP. G-protein-coupled OX1 orexin/hcrtr-1 hypocretin receptors induce caspase-dependent and -independent cell death through p38 mitogen-/stress-activated protein kinase. J Biol Chem 2006;281(2):834-842.
58. Peltonen HM, Magga JM, Bart G, Turunen PM, Antikainen MS, Kukkonen JP, Akerman KE. Involvement of TRPC3 channels in calcium oscillations mediated by OX(1) orexin receptors. Biochem Biophys Res Commun 2009;385(3):408-412.
59. Turunen PM, Ekholm ME, Somerharju P, Kukkonen JP. Arachidonic acid release mediated by OX1 orexin receptors. Br J Pharmacol 2010;159(1):212-221.
60. Johansson L, Ekholm ME, Kukkonen JP. Multiple phospholipase activation by OX(1) orexin/hypocretin receptors. Cell Mol Life Sci 2008;65(12):1948-1956.
61. Rouet-Benzineb P, Rouyer-Fessard C, Jarry A, Avondo V, Pouzet C, Yanagisawa M, Laboisse C, Laburthe M, Voisin T. Orexins acting at native OX(1) receptor in colon cancer and neuroblastoma cells or at recombinant OX(1) receptor suppress cell growth by inducing apoptosis. J Biol Chem 2004;279(44):45875-45886.
62. Shih CD, Chuang YC. Nitric oxide and GABA mediate bi-directional cardiovascular effects of orexin in the nucleus tractus solitarii of rats. Neuroscience 2007;149(3):625-635.
63. Skrzypski M, T Le T, Kaczmarek P, Pruszynska-Oszmalek E, Pietrzak P, Szczepankiewicz D, Kolodziejski PA, Sassek M, Arafat A, Wiedenmann B, Nowak KW, Strowski MZ. Orexin A stimulates glucose uptake, lipid accumulation and adiponectin secretion from 3T3-L1 adipocytes and isolated primary rat adipocytes. Diabetologia 2011;54(7):1841-1852.
64. Yoshida Y, Fujiki N, Nakajima T, Ripley B, Matsumura H, Yoneda H, Mignot E, Nishino S. Fluctuation of extracellular hypocretin-1 (orexin A) levels in the rat in relation to the light-dark cycle and sleep-wake activities. Eur J Neurosci 2001;14(7):1075-1081.
65. Lee MG, Hassani OK, Jones BE. Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J Neurosci 2005;25(28):6716-6720.
66. Bourgin P, Huitron-Resendiz S, Spier AD, Fabre V, Morte B, Criado JR, Sutcliffe JG, Henriksen SJ, de Lecea L. Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci 2000;20(20):7760-7765.
67. Willie JT, Chemelli RM, Sinton CM, Tokita S, Williams SC, Kisanuki YY, Marcus JN, Lee C, Elmquist JK, Kohlmeier KA, Leonard CS, Richardson JA, Hammer RE, Yanagisawa M. Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: Molecular genetic dissection of non-REM and REM sleep regulatory processes. Neuron 2003;38(5):715-730.
68. Gerashchenko D, Kohls MD, Greco M, Waleh NS, Salin-Pascual R, Kilduff TS, Lappi DA, Shiromani PJ. Hypocretin-2-saporin lesions of the lateral hypothalamus produce narcoleptic-like sleep behavior in the rat. J Neurosci 2001;21(18):7273-7283.
69. Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 2007;450(7168):420-424.
70. Tsunematsu T, Kilduff TS, Boyden ES, Takahashi S, Tominaga M, Yamanaka A. Acute optogenetic silencing of orexin/hypocretin neurons induces slow-wave sleep in mice. J Neurosci 2011;31(29):10529-10539.
71. Xia J, Chen X, Song C, Ye J, Yu Z, Hu Z. Postsynaptic excitation of prefrontal cortical pyramidal neurons by hypocretin-1/orexin A through the inhibition of potassium currents. J Neurosci Res 2005;82(5):729-736.
72. Hoang QV, Zhao P, Nakajima S, Nakajima Y. Orexin (hypocretin) effects on constitutively active inward rectifier K+ channels in cultured nucleus basalis neurons. J Neurophysiol 2004;92(6):3183-3191.
73. Wu M, Zaborszky L, Hajszan T, van den Pol AN, Alreja M. Hypocretin/orexin innervation and excitation of identified septohippocampal cholinergic neurons. J Neurosci 2004;24(14):3527-3536.
74. Bayer L, Eggermann E, Saint-Mleux B, Machard D, Jones BE, Muhlethaler M, Serafin M. Selective action of orexin (hypocretin) on nonspecific thalamocortical projection neurons. J Neurosci 2002;22(18):7835-7839.
75. Govindaiah G, Cox CL. Modulation of thalamic neuron excitability by orexins. Neuropharmacology 2006;51(3):414-425.
76. Hoang QV, Bajic D, Yanagisawa M, Nakajima S, Nakajima Y. Effects of orexin (hypocretin) on GIRK channels. J Neurophysiol 2003;90(2):693-702.
77. Ivanov A, Aston-Jones G. Hypocretin/orexin depolarizes and decreases potassium conductance in locus coeruleus neurons. Neuroreport 2000;11(8):1755-1758.
78. Murai Y, Akaike T. Orexins cause depolarization via nonselective cationic and K+ channels in isolated locus coeruleus neurons. Neurosci Res 2005;51(1):55-65.
79. Brown RE, Sergeeva O, Eriksson KS, Haas HL. Orexin A excites serotonergic neurons in the dorsal raphe nucleus of the rat. Neuropharmacology 2001;40(3):457-459.
80. Kim J, Nakajima K, Oomura Y, Wayner MJ, Sasaki K. Orexin-A and ghrelin depolarize the same pedunculopontine tegmental neurons in rats: An in vitro study. Peptides 2009;30(7):1328-1335.
81. Kim J, Nakajima K, Oomura Y, Wayner MJ, Sasaki K. Electrophysiological effects of orexins/hypocretins on pedunculopontine tegmental neurons in rats: An in vitro study. Peptides 2009;30(2):191-209.
82. Xia JX, Fan SY, Yan J, Chen F, Li Y, Yu ZP, Hu ZA. Orexin A-induced extracellular calcium influx in prefrontal cortex neurons involves L-type calcium channels. J Physiol Biochem 2009;65(2):125-136.
83. Kohlmeier KA, Inoue T, Leonard CS. Hypocretin/orexin peptide signaling in the ascending arousal system: Elevation of intracellular calcium in the mouse dorsal raphe and laterodorsal tegmentum. J Neurophysiol 2004;92(1):221-235.
84. Yamanaka A, Tabuchi S, Tsunematsu T, Fukazawa Y, Tominaga M. Orexin directly excites orexin neurons through orexin 2 receptor. J Neurosci 2010;30(38):12642-12652.
85. Liu RJ, van den Pol AN, Aghajanian GK. Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J Neurosci 2002;22(21):9453-9464.
86. 2+ transients mediated by L-type calcium channels. J Neurophysiol 2008;100(4):2265-2281.
87. Wu M, Zhang Z, Leranth C, Xu C, van den Pol AN, Alreja M. Hypocretin increases impulse flow in the septohippocampal GABAergic pathway: Implications for arousal via a mechanism of hippocampal disinhibition. J Neurosci 2002;22(17):7754-7765.
88. Eriksson KS, Sergeeva O, Brown RE, Haas HL. Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus. J Neurosci 2001;21(23):9273-9279.
89. Brevig HN, Watson CJ, Lydic R, Baghdoyan HA. Hypocretin and GABA interact in the pontine reticular formation to increase wakefulness. Sleep 2010;33(10):1285-1293.
90. Yan J, He C, Xia JX, Zhang D, Hu ZA. Orexin-A excites pyramidal neurons in layer 2/3 of the rat prefrontal cortex. Neurosci Lett 2012;520(1):92-97.
91. Dube MG, Kalra SP, Kalra PS. Food intake elicited by central administration of orexins/hypocretins: Identification of hypothalamic sites of action. Brain Res 1999;842(2):473-477.
92. Sweet DC, Levine AS, Billington CJ, Kotz CM. Feeding response to central orexins. Brain Res 1999;821(2):535-538.
93. Baird JP, Choe A, Loveland JL, Beck J, Mahoney CE, Lord JS, Grigg LA. Orexin-A hyperphagia: Hindbrain participation in consummatory feeding responses. Endocrinology 2009;150(3):1202-1216.
94. Yamada H, Okumura T, Motomura W, Kobayashi Y, Kohgo Y. Inhibition of food intake by central injection of anti-orexin antibody in fasted rats. Biochem Biophys Res Commun 2000;267(2):527-531.
95. Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, Sugiyama F, Yagami K, Goto K, Yanagisawa M, Sakurai T. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 2001;30(2):345-354.
96. Yamanaka A, Kunii K, Nambu T, Tsujino N, Sakai A, Matsuzaki I, Miwa Y, Goto K, Sakurai T. Orexin-induced food intake involves neuropeptide Y pathway. Brain Res 2000;859(2):404-409.
97. van den Top M, Lee K, Whyment AD, Blanks AM, Spanswick D. Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nat Neurosci 2004;7(5):493-494.
98. Thorpe AJ, Kotz CM. Orexin A in the nucleus accumbens stimulates feeding and locomotor activity. Brain Res 2005;1050(1-2):156-162.
99. Karteris E, Machado RJ, Chen J, Zervou S, Hillhouse EW, Randeva HS. Food deprivation differentially modulates orexin receptor expression and signaling in rat hypothalamus and adrenal cortex. Am J Physiol Endocrinol Metab 2005;288(6):E1089-E1100.
100. Yamanaka A, Beuckmann CT, Willie JT, Hara J, Tsujino N, Mieda M, Tominaga M, Yagami K, Sugiyama F, Goto K, Yanagisawa M, Sakurai T. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 2003;38(5):701-713.
101. Burdakov D, Gerasimenko O, Verkhratsky A. Physiological changes in glucose differentially modulate the excitability of hypothalamic melanin-concentrating hormone and orexin neurons in situ. J Neurosci 2005;25(9):2429-2433.
102. + channels mediate inhibition of orexin neurons by glucose. Neuron 2006;50(5):711-722.
103. Gonzalez JA, Jensen LT, Doyle SE, Miranda-Anaya M, Menaker M, Fugger L, Bayliss DA, Burdakov D. Deletion of TASK1 and TASK3 channels disrupts intrinsic excitability but does not abolish glucose or pH responses of orexin/hypocretin neurons. Eur J Neurosci 2009;30(1):57-64.
104. Borgland SL, Chang SJ, Bowers MS, Thompson JL, Vittoz N, Floresco SB, Chou J, Chen BT, Bonci A. Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers. J Neurosci 2009;29(36):11215-11225.
105. Sharf R, Sarhan M, Brayton CE, Guarnieri DJ, Taylor JR, DiLeone RJ. Orexin signaling via the orexin 1 receptor mediates operant responding for food reinforcement. Biol Psychiatry 2010;67(8):753-760.
106. Choi DL, Davis JF, Fitzgerald ME, Benoit SC. The role of orexin-A in food motivation, reward-based feeding behavior and food-induced neuronal activation in rats. Neuroscience 2010;167(1):11-20.
107. Gulia KK, Mallick HN, Kumar VM. Orexin A (hypocretin-1) application at the medial preoptic area potentiates male sexual behavior in rats. Neuroscience 2003;116(4):921-923.
108. Di Sebastiano AR, Wilson-Perez HE, Lehman MN, Coolen LM. Lesions of orexin neurons block conditioned place preference for sexual behavior in male rats. Horm Behav 2011;59(1):1-8.
109. Ponz A, Khatami R, Poryazova R, Werth E, Boesiger P, Bassetti CL, Schwartz S. Abnormal activity in reward brain circuits in human narcolepsy with cataplexy. Ann Neurol 2010;67(2):190-200.
110. Korotkova TM, Sergeeva OA, Eriksson KS, Haas HL, Brown RE. Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J Neurosci 2003;23(1):7-11.
111. Borgland SL, Taha SA, Sarti F, Fields HL, Bonci A. Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 2006;49(4):589-601.
112. McFarland K, Kalivas PW. The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 2001;21(21):8655-8663.
113. McFarland K, Davidge SB, Lapish CC, Kalivas PW. Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. J Neurosci 2004;24(7):1551-1560.
114. Carr DB, Sesack SR. Projections from the rat prefrontal cortex to the ventral tegmental area: Target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons. J Neurosci 2000;20(10):3864-3873.
115. Zhang GC, Mao LM, Liu XY, Wang JQ. Long-lasting up-regulation of orexin receptor type 2 protein levels in the rat nucleus accumbens after chronic cocaine administration. J Neurochem 2007;103(1):400-407.
116. Voorhees CM, Cunningham CL. Involvement of the orexin/hypocretin system in ethanol conditioned place preference. Psychopharmacology (Berl) 2011;214(4):805-818.
117. Gozzi A, Turrini G, Piccoli L, Massagrande M, Amantini D, Antolini M, Martinelli P, Cesari N, Montanari D, Tessari M, Corsi M, Bifone A. Functional magnetic resonance imaging reveals different neural substrates for the effects of orexin-1 and orexin-2 receptor antagonists. PLoS One 2011;6(1):e16406.
118. Martin G, Fabre V, Siggins GR, de Lecea L. Interaction of the hypocretins with neurotransmitters in the nucleus accumbens. Regul Pept 2002;104(1-3):111-117.
119. Mukai K, Kim J, Nakajima K, Oomura Y, Wayner MJ, Sasaki K. Electrophysiological effects of orexin/hypocretin on nucleus accumbens shell neurons in rats: An in vitro study. Peptides 2009;30(8):1487-1496.
120. Harris GC, Aston-Jones G. Arousal and reward: A dichotomy in orexin function. Trends Neurosci 2006;29(10):571-577.
121. Fadel J, Bubser M, Deutch AY. Differential activation of orexin neurons by antipsychotic drugs associated with weight gain. J Neurosci 2002;22(15):6742-6746.
122. Estabrooke IV, McCarthy MT, Ko E, Chou TC, Chemelli RM, Yanagisawa M, Saper CB, Scammell TE. FOS expression in orexin neurons varies with behavioral state. J Neurosci 2001;21(5):1656-1662.
123. Harris GC, Wimmer M, Aston-Jones G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 2005;437(7058):556-559.
124. Johnson PL, Truitt W, Fitz SD, Minick PE, Dietrich A, Sanghani S, Traskman-Bendz L, Goddard AW, Brundin L, Shekhar A. A key role for orexin in panic anxiety. Nat Med 2010;16(1):111-115.
125. Nollet M, Gaillard P, Minier F, Tanti A, Belzung C, Leman S. Activation of orexin neurons in dorsomedial/perifornical hypothalamus and antidepressant reversal in a rodent model of depression. Neuropharmacology 2011;61(1-2):336-346.
126. Johnson PL, Samuels BC, Fitz SD, Federici LM, Hammes N, Early MC, Truitt W, Lowry CA, Shekhar A. Orexin 1 receptors are a novel target to modulate panic responses and the panic brain network. Physiol Behav 2012;107(5):733-742.
127. Spinazzi R, Andreis PG, Rossi GP, Nussdorfer GG. Orexins in the regulation of the hypothalamic-pituitary-adrenal axis. Pharmacol Rev 2006;58(1):46-57.
128. Ida T, Nakahara K, Murakami T, Hanada R, Nakazato M, Murakami N. Possible involvement of orexin in the stress reaction in rats. Biochem Biophys Res Commun 2000;270(1):318-323.
129. Winsky-Sommerer R, Yamanaka A, Diano S, Borok E, Roberts AJ, Sakurai T, Kilduff TS, Horvath TL, de Lecea L. Interaction between the corticotropin-releasing factor system and hypocretins (orexins): A novel circuit mediating stress response. J Neurosci 2004;24(50):11439-11448.
130. Furlong TM, Vianna DM, Liu L, Carrive P. Hypocretin/orexin contributes to the expression of some but not all forms of stress and arousal. Eur J Neurosci 2009;30(8):1603-1614.
131. Kayaba Y, Nakamura A, Kasuya Y, Ohuchi T, Yanagisawa M, Komuro I, Fukuda Y, Kuwaki T. Attenuated defense response and low basal blood pressure in orexin knockout mice. Am J Physiol Regul Integr Comp Physiol 2003;285(3):R581-R593.
132. Smith PM, Connolly BC, Ferguson AV. Microinjection of orexin into the rat nucleus tractus solitarius causes increases in blood pressure. Brain Res 2002;950(1-2):261-267.
133. Smith BN, Davis SF, Van den Pol AN, Xu W. Selective enhancement of excitatory synaptic activity in the rat nucleus tractus solitarius by hypocretin 2. Neuroscience 2002;115(3):707-714.
134. Shahid IZ, Rahman AA, Pilowsky PM. Intrathecal orexin A increases sympathetic outflow and respiratory drive, enhances baroreflex sensitivity and blocks the somato-sympathetic reflex. Br J Pharmacol 2011;162(4):961-973.
135. Zhang W, Sakurai T, Fukuda Y, Kuwaki T. Orexin neuron-mediated skeletal muscle vasodilation and shift of baroreflex during defense response in mice. Am J Physiol Regul Integr Comp Physiol 2006;290(6):R1654-1663.
136. Jaszberenyi M, Bujdoso E, Pataki I, Telegdy G. Effects of orexins on the hypothalamic-pituitary-adrenal system. J Neuroendocrinol 2000;12(12):1174-1178.
137. Kuru M, Ueta Y, Serino R, Nakazato M, Yamamoto Y, Shibuya I, Yamashita H. Centrally administered orexin/hypocretin activates HPA axis in rats. Neuroreport 2000;11(9):1977-1980.
138. Malendowicz LK, Hochol A, Ziolkowska A, Nowak M, Gottardo L, Nussdorfer GG. Prolonged orexin administration stimulates steroid-hormone secretion, acting directly on the rat adrenal gland. Int J Mol Med 2001;7(4):401-404.
139. Ziolkowska A, Spinazzi R, Albertin G, Nowak M, Malendowicz LK, Tortorella C, Nussdorfer GG. Orexins stimulate glucocorticoid secretion from cultured rat and human adrenocortical cells, exclusively acting via the OX1 receptor. J Steroid Biochem Mol Biol 2005;96(5):423-429.
140. Jaeger LB, Farr SA, Banks WA, Morley JE. Effects of orexin-A on memory processing. Peptides 2002;23(9):1683-1688.
141. Telegdy G, Adamik A. The action of orexin A on passive avoidance learning. Involvement of transmitters. Regul Pept 2002;104(1-3):105-110.
142. Akbari E, Motamedi F, Naghdi N, Noorbakhshnia M. The effect of antagonization of orexin 1 receptors in CA1 and dentate gyrus regions on memory processing in passive avoidance task. Behav Brain Res 2008;187(1):172-177.
143. Akbari E, Naghdi N, Motamedi F. Functional inactivation of orexin 1 receptors in CA1 region impairs acquisition, consolidation and retrieval in Morris water maze task. Behav Brain Res 2006;173(1):47-52.
144. Akbari E, Naghdi N, Motamedi F. The selective orexin 1 receptor antagonist SB-334867-A impairs acquisition and consolidation but not retrieval of spatial memory in Morris water maze. Peptides 2007;28(3):650-656.
145. Smith HR, Pang KC. Orexin-saporin lesions of the medial septum impair spatial memory. Neuroscience 2005;132(2):261-271.
146. Oomura Y, Aou S, Fukunaga K, Moriguchi S, Sasaki K. Prandial increases of leptin and orexin in the brain modulate spatial learning and memory. Ross Fiziol Zh Im I M Sechenova 2009;95(12):1373-1385.
147. Aou S, Li XL, Li AJ, Oomura Y, Shiraishi T, Sasaki K, Imamura T, Wayner MJ. Orexin-A (hypocretin-1) impairs Morris water maze performance and CA1-Schaffer collateral long-term potentiation in rats. Neuroscience 2003;119(4):1221-1228.
148. Mediavilla C, Cabello V, Risco S. SB-334867-A, a selective orexin-1 receptor antagonist, enhances taste aversion learning and blocks taste preference learning in rats. Pharmacol Biochem Behav 2011;98(3):385-391.
149. Dietrich H, Jenck F. Intact learning and memory in rats following treatment with the dual orexin receptor antagonist almorexant. Psychopharmacology (Berl) 2010;212(2):145-154.
150. He C, Chen F, Li B, Hu Z. Neurophysiology of HCN channels: From cellular functions to multiple regulations. Prog Neurobiol 2014;112:1-23.
151. Boschen KE, Fadel JR, Burk JA. Systemic and intrabasalis administration of the orexin-1 receptor antagonist, SB-334867, disrupts attentional performance in rats. Psychopharmacology (Berl) 2009;206(2):205-213.
152. Deadwyler SA, Porrino L, Siegel JM, Hampson RE. Systemic and nasal delivery of orexin-A (hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci 2007;27(52):14239-14247.
153. Jeong Y, Holden JE. The role of spinal orexin-1 receptors in posterior hypothalamic modulation of neuropathic pain. Neuroscience 2009;159(4):1414-1421.
154. Julliard AK, Chaput MA, Apelbaum A, Aime P, Mahfouz M, Duchamp-Viret P. Changes in rat olfactory detection performance induced by orexin and leptin mimicking fasting and satiation. Behav Brain Res 2007;183(2):123-129.
155. Kotz CM, Wang C, Teske JA, Thorpe AJ, Novak CM, Kiwaki K, Levine JA. Orexin A mediation of time spent moving in rats: Neural mechanisms. Neuroscience 2006;142(1):29-36.
156. Kotz CM, Teske JA, Levine JA, Wang C. Feeding and activity induced by orexin A in the lateral hypothalamus in rats. Regul Pept 2002;104(1-3):27-32.
157. Wang J, Osaka T, Inoue S. Orexin-A-sensitive site for energy expenditure localized in the arcuate nucleus of the hypothalamus. Brain Res 2003;971(1):128-134.
158. Lopez M, Nogueiras R, Tena-Sempere M, Dieguez C. Orexins (hypocretins) actions on the GHRH/somatostatin-GH axis. Acta Physiol (Oxf) 2010;198(3):325-334.
159. Eliassi A, Nazari M, Naghdi N. Role of the ventromedial hypothalamic orexin-1 receptors in regulation of gastric acid secretion in conscious rats. J Neuroendocrinol 2009;21(3):177-182.
160. Kobayashi M, Nomura M, Fujihara H, Suzuki H, Otsubo H, Nishii H, Fujimoto N, Matsumoto T, Ueta Y. Involvement of orexin-A on micturition reflex in normal and cyclophosphamide-induced cystitis bladder in rat. Peptides 2009;30(12):2348-2356.
161. Nurmio M, Tena-Sempere M, Toppari J. Orexins and the regulation of the hypothalamic-pituitary-testicular axis. Acta Physiol (Oxf) 2010;198(3):349-354.
162. Zhang W, Fukuda Y, Kuwaki T. Respiratory and cardiovascular actions of orexin-A in mice. Neurosci Lett 2005;385(2):131-136.
163. Buysse DJ. Insomnia. JAMA 2013;309(7):706-716.
164. Nagai M, Hoshide S, Nishikawa M, Shimada K, Kario K. Sleep duration and insomnia in the elderly: Associations with blood pressure variability and carotid artery remodeling. Am J Hypertens 2013;26(8):981-989.
165. Troxel WM, Buysse DJ, Matthews KA, Kip KE, Strollo PJ, Hall M, Drumheller O, Reis SE. Sleep symptoms predict the development of the metabolic syndrome. Sleep 2010;33(12):1633-1640.
166. Ohayon MM. Epidemiology of insomnia: What we know and what we still need to learn. Sleep Med Rev 2002;6(2):97-111.
167. Prober DA, Rihel J, Onah AA, Sung RJ, Schier AF. Hypocretin/orexin overexpression induces an insomnia-like phenotype in zebrafish. J Neurosci 2006;26(51):13400-13410.
168. Nofzinger EA, Buysse DJ, Germain A, Price JC, Miewald JM, Kupfer DJ. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatr 2004;161(11):2126-2129.
169. Bonnet MH, Arand DL. Activity, arousal, and the MSLT in patients with insomnia. Sleep 2000;23(2):205-212.
170. Yokogawa T, Marin W, Faraco J, Pezeron G, Appelbaum L, Zhang J, Rosa F, Mourrain P, Mignot E. Characterization of sleep in zebrafish and insomnia in hypocretin receptor mutants. PLoS Biol 2007;5(10):e277.
171. Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S, Vankova J, Black J, Harsh J, Bassetti C, Schrader H, Nishino S. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 2002;59(10):1553-1562.
172. Schenck CH, Bundlie SR, Mignot E, Mahowald MW. Normal hypocretin-1 (orexin-A) cerebrospinal fluid level in a previously reported case of severe, life-long insomnia with motor hyperactivity. Sleep Med 2003;4(3):251.
173. Gerashchenko D, Blanco-Centurion CA, Miller JD, Shiromani PJ. Insomnia following hypocretin2-saporin lesions of the substantia nigra. Neuroscience 2006;137(1):29-36.
174. Aldrich MS, Reynolds PR. Narcolepsy and the hypocretin receptor 2 gene. Neuron 1999;23(4):625-626.
175. Takei Y, Komada Y, Namba K, Sasai T, Nakamura M, Sugiura T, Hayashida K, Inoue Y. Differences in findings of nocturnal polysomnography and multiple sleep latency test between narcolepsy and idiopathic hypersomnia. Clin Neurophysiol 2012;123(1):137-141.
176. Nakamura M, Kanbayashi T, Sugiura T, Inoue Y. Relationship between clinical characteristics of narcolepsy and CSF orexin-A levels. J Sleep Res 2011;20(1 Pt 1):45-49.
177. Thannickal TC, Nienhuis R, Siegel JM. Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy. Sleep 2009;32(8):993-998.
178. Nakamura M, Nishida S, Hayashida K, Ueki Y, Dauvilliers Y, Inoue Y. Differences in brain morphological findings between narcolepsy with and without cataplexy. PLoS One 2013;8(11):e81059.
179. Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, Cornford M, Siegel JM. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000;27(3):469-474.
180. Thannickal TC, Siegel JM, Nienhuis R, Moore RY. Pattern of hypocretin (orexin) soma and axon loss, and gliosis, in human narcolepsy. Brain Pathol 2003;13(3):340-351.
181. Hallmayer J, Faraco J, Lin L, Hesselson S, Winkelmann J, Kawashima M, Mayer G, Plazzi G, Nevsimalova S, Bourgin P, Hong SSC, Honda Y, Honda M, Hogl B, Longstreth WT, Montplaisir J, Kemlink D, Einen M, Chen J, Musone SL, Akana M, Miyagawa T, Duan J, Desautels A, Erhardt C, Hesla PE, Poli F, Frauscher B, Jeong JH, Lee SP, Ton TGN, Kvale M, Kolesar L, Dobrovolna M, Nepom GT, Salomon D, Wichmann HE, Rouleau GA, Gieger C, Levinson DF, Gejman PV, Meitinger T, Young T, Peppard P, Tokunaga K, Kwok PY, Risch N, Mignot E. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nat Genet 2009;41(6):708-711.
182. Faraco J, Lin L, Kornum BR, Kenny EE, Trynka G, Einen M, Rico TJ, Lichtner P, Dauvilliers Y, Arnulf I, Lecendreux M, Javidi S, Geisler P, Mayer G, Pizza F, Poli F, Plazzi G, Overeem S, Lammers GJ, Kemlink D, Sonka K, Nevsimalova S, Rouleau G, Desautels A, Montplaisir J, Frauscher B, Ehrmann L, Hogl B, Jennum P, Bourgin P, Peraita-Adrados R, Iranzo A, Bassetti C, Chen WM, Concannon P, Thompson SD, Damotte V, Fontaine B, Breban M, Gieger C, Klopp N, Deloukas P, Wijmenga C, Hallmayer J, Onengut-Gumuscu S, Rich SS, Winkelmann J, Mignot E. ImmunoChip study implicates antigen presentation to T cells in narcolepsy. PLoS Genet 2013;9(2):e1003270.
183. Hallmayer J, Faraco J, Lin L, Hesselson S, Winkelmann J, Kawashima M, Mayer G, Plazzi G, Nevsimalova S, Bourgin P, Hong SC, Honda Y, Honda M, Hogl B, Longstreth WT, Montplaisir J, Kemlink D, Einen M, Chen J, Musone SL, Akana M, Miyagawa T, Duan JB, Desautels A, Erhardt C, Hesla PE, Poli F, Frauscher B, Jeong JH, Lee SP, Ton TGN, Kvale M, Kolesar L, Dobrovolna M, Nepom GT, Salomon D, Wichmann HE, Rouleau GA, Gieger C, Levinson DF, Gejman PV, Meitinger T, Young T, Peppard P, Tokunaga K, Kwok PY, Risch N, Mignot E. Narcolepsy is strongly associated with the T-cell receptor alpha locus (vol 41, pg 708, 2009). Nat Genet 2009;41(7):859-859.
184. 4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy. Sci Transl Med 2013;5(216):216ra176.
185. Black JL, 3rd, Silber MH, Krahn LE, Fredrickson PA, Pankratz VS, Avula R, Walker DL, Slocumb NL. Analysis of hypocretin (orexin) antibodies in patients with narcolepsy. Sleep 2005;28(4):427-431.
186. Tanaka S, Honda Y, Inoue Y, Honda M. Detection of autoantibodies against hypocretin, hcrtrl, and hcrtr2 in narcolepsy: Anti-Hcrt system antibody in narcolepsy. Sleep 2006;29(5):633-638.
187. Dalal MA, Schuld A, Haack M, Uhr M, Geisler P, Eisensehr I, Noachtar S, Pollmacher T. Normal plasma levels of orexin A (hypocretin-1) in narcoleptic patients. Neurology 2001;56(12):1749-1751.
188. Kanbayashi T, Inoue Y, Chiba S, Aizawa R, Saito Y, Tsukamoto H, Fujii Y, Nishino S, Shimizu T. CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia. J Sleep Res 2002;11(1):91-93.
189. Nishino S, Ripley B, Overeem S, Nevsimalova S, Lammers GJ, Vankova J, Okun M, Rogers W, Brooks S, Mignot E. Low cerebrospinal fluid hypocretin (Orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 2001;50(3):381-388.
190. Ebrahim IO, Sharief MK, de Lacy S, Semra YK, Howard RS, Kopelman MD, Williams AJ. Hypocretin (orexin) deficiency in narcolepsy and primary hypersomnia. J Neurol Neurosurg Psychiatry 2003;74(1):127-130.
191. Arii J, Kanbayashi T, Tanabe Y, Sawaishi Y, Kimura S, Watanabe A, Mishima K, Hishikawa Y, Shimizu T, Nishino S. CSF hypocretin-1 (orexin-A) levels in childhood narcolepsy and neurologic disorders. Neurology 2004;63(12):2440-2442.
192. Oka Y, Inoue Y, Kanbayashi T, Kuroda K, Miyamoto M, Miyamoto T, Ikeda A, Shimizu T, Hishikawa Y, Shibasaki H. Narcolepsy without cataplexy: 2 subtypes based on CSF hypocretin-1/orexin-A findings. Sleep 2006;29(11):1439-1443.
193. Baumann CR, Bassetti CL. Hypocretins (orexins) and sleep-wake disorders. Lancet Neurol 2005;4(10):673-682.
194. Ripley B, Fujiki N, Okura M, Mignot E, Nishino S. Hypocretin levels in sporadic and familial cases of canine narcolepsy. Neurobiol Dis 2001;8(3):525-534.
195. Tsukamoto H, Ishikawa T, Fujii Y, Fukumizu M, Sugai K, Kanbayashi T. Undetectable levels of CSF hypocretin-1 (orexin-A) in two prepubertal boys with narcolepsy. Neuropediatrics 2002;33(1):51-52.
196. Kubota H, Kanbayashi T, Tanabe Y, Ito M, Takanashi J, Kohno Y, Shimizu T. Decreased cerebrospinal fluid hypocretin-1 levels near the onset of narcolepsy in 2 prepubertal children. Sleep 2003;26(5):555-557.
197. Higuchi S, Usui A, Murasaki M, Matsushita S, Nishioka N, Yoshino A, Matsui T, Muraoka H, Ishizuka Y, Kanba S, Sakurai T. Plasma orexin-A is lower in patients with narcolepsy. Neurosci Lett 2002;318(2):61-64.
198. Fairburn CG, Harrison PJ. Eating disorders. Lancet 2003;361(9355):407-416.
199. Kaye WH, Frank GK, Bailer UF, Henry SE. Neurobiology of anorexia nervosa: Clinical implications of alterations of the function of serotonin and other neuronal systems. Int J Eat Disorder 2005;37:S15-S19.
200. Barbarich NC, Kaye WH, Jimerson D. Neurotransmitter and imaging studies in anorexia nervosa: New targets for treatment. Curr Drug Targets CNS Neurol Disord 2003;2(1):61-72.
201. Bosanac P, Norman T, Burrows G, Beumont P. Serotonergic and dopaminergic systems in anorexia nervosa: A role for atypical antipsychotics? Aust N Z J Psychiatry 2005;39(3):146-153.
202. Janas-Kozik M, Stachowicz M, Krupka-Matuszczyk I, Szymszal J, Krysta K, Janas A, Rybakowski JK. Plasma levels of leptin and orexin A in the restrictive type of anorexia nervosa. Regul Pept 2011;168(1-3):5-9.
203. Bronsky J, Nedvidkova J, Krasnicanova H, Vesela M, Schmidtova J, Koutek J, Kellermayer R, Chada M, Kabelka Z, Hrdlicka M, Nevoral J, Prusa R. Changes of orexin A plasma levels in girls with anorexia nervosa during eight weeks of realimentation. Int J Eat Disord 2011;44(6):547-552.
204. Nevsimalova S, Vankova J, Stepanova I, Seemanova E, Mignot E, Nishino S. Hypocretin deficiency in Prader-Willi syndrome. Eur J Neurol 2005;12(1):70-72.
205. Fronczek R, Lammers GJ, Balesar R, Unmehopa UA, Swaab DF. The number of hypothalamic hypocretin (orexin) neurons is not affected in Prader-Willi syndrome. J Clin Endocrinol Metab 2005;90(9):5466-5470.
206. Mahler SV, Smith RJ, Moorman DE, Sartor GC, Aston-Jones G. Multiple roles for orexin/hypocretin in addiction. Prog Brain Res 2012;198:79-121.
207. Sharf R, Sarhan M, Dileone RJ. Role of orexin/hypocretin in dependence and addiction. Brain Res 2010;1314:130-138.
208. Aston-Jones G, Smith RJ, Moorman DE, Richardson KA. Role of lateral hypothalamic orexin neurons in reward processing and addiction. Neuropharmacology 2009;56 Suppl 1:112-121.
209. Georgescu D, Zachariou V, Barrot M, Mieda M, Willie JT, Eisch AJ, Yanagisawa M, Nestler EJ, DiLeone RJ. Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal. J Neurosci 2003;23(8):3106-3111.
210. Boutrel B, Kenny PJ, Specio SE, Martin-Fardon R, Markou A, Koob GF, de Lecea L. Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci USA 2005;102(52):19168-19173.
211. Smith RJ, See RE, Aston-Jones G. Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking. Eur J Neurosci 2009;30(3):493-503.
212. Espana RA, Melchior JR, Roberts DC, Jones SR. Hypocretin 1/orexin A in the ventral tegmental area enhances dopamine responses to cocaine and promotes cocaine self-administration. Psychopharmacology (Berl) 2011;214(2):415-426.
213. Lawrence AJ, Cowen MS, Yang HJ, Chen F, Oldfield B. The orexin system regulates alcohol-seeking in rats. Br J Pharmacol 2006;148(6):752-759.
214. Jupp B, Krivdic B, Krstew E, Lawrence AJ. The orexin(1) receptor antagonist SB-334867 dissociates the motivational properties of alcohol and sucrose in rats. Brain Res 2011;1391:54-59.
215. Richards JK, Simms JA, Steensland P, Taha SA, Borgland SL, Bonci A, Bartlett SE. Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats. Psychopharmacology (Berl) 2008;199(1):109-117.
216. Plaza-Zabala A, Martin-Garcia E, de Lecea L, Maldonado R, Berrendero F. Hypocretins regulate the anxiogenic-like effects of nicotine and induce reinstatement of nicotine-seeking behavior. J Neurosci 2010;30(6):2300-2310.
217. Marchant NJ HA, McNally GP. Lateral hypothalamus is required for context-induced reinstatement of extinguished reward seeking. J Neurosci 2009;29(5):1331-1342.
218. Smith R, See R, Aston-Jones G. The orexin-1 receptor antagonist SB-334867 blocks cue induced reinstatement of cocaine-seeking. Neuroscience Meeting Planner Online, Program No 916.1, 2007.
219. Zheng H, Patterson LM, Berthoud HR. Orexin signaling in the ventral tegmental area is required for high-fat appetite induced by opioid stimulation of the nucleus accumbens. J Neurosci 2007;27(41):11075-11082.
220. Moorman DE, Aston-Jones G. Orexin/hypocretin modulates response of ventral tegmental dopamine neurons to prefrontal activation: diurnal influences. J Neurosci 2010;30(46):15585-15599.
221. Narita M, Nagumo Y, Hashimoto S, Khotib J, Miyatake M, Sakurai T, Yanagisawa M, Nakamachi T, Shioda S, Suzuki T. Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine. J Neurosci 2006;26(2):398-405.
222. James MH, Charnley JL, Levi EM, Jones E, Yeoh JW, Smith DW, Dayas CV. Orexin-1 receptor signalling within the ventral tegmental area, but not the paraventricular thalamus, is critical to regulating cue-induced reinstatement of cocaine-seeking. Int J Neuropsychopharmacol 2011;14(5):684-690.
223. Taslimi Z, Haghparast A, Hassanpour-Ezatti M, Safari MS. Chemical stimulation of the lateral hypothalamus induces conditioned place preference in rats: Involvement of OX1 and CB1 receptors in the ventral tegmental area. Behav Brain Res 2011;217(1):41-46.
224. Quarta D, Valerio E, Hutcheson DM, Hedou G, Heidbreder C. The orexin-1 receptor antagonist SB-334867 reduces amphetamine-evoked dopamine outflow in the shell of the nucleus accumbens and decreases the expression of amphetamine sensitization. Neurochem Int 2010;56(1):11-15.
225. Mori K, Kim J, Sasaki K. Electrophysiological effects of orexin-B and dopamine on rat nucleus accumbens shell neurons in vitro. Peptides 2011;32(2):246-252.
226. Sharf R, Sarhan M, Dileone RJ. Orexin mediates the expression of precipitated morphine withdrawal and concurrent activation of the nucleus accumbens shell. Biol Psychiatry 2008;64(3):175-183.
227. Millan EZ, Furlong TM, McNally GP. Accumbens shell-hypothalamus interactions mediate extinction of alcohol seeking. J Neurosci 2010;30(13):4626-4635.
228. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS. The epidemiology of major depressive disorder: Results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;289(23):3095-3105.
229. Kupfer DJ, Frank E, Phillips ML. Major depressive disorder: New clinical, neurobiological, and treatment perspectives. Lancet 2012;379(9820):1045-1055.
230. Benazzi F. Bipolar disorder-Focus on bipolar II disorder and mixed depression. Lancet 2007;369(9565):935-945.
231. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature 2008;455(7215):894-902.
232. Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron 2002;34(1):13-25.
233. Rubin RT, Phillips JJ, McCracken JT, Sadow TF. Adrenal gland volume in major depression: Relationship to basal and stimulated pituitary-adrenal cortical axis function. Biol Psychiatry 1996;40(2):89-97.
234. Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 2000;23(5):477-501.
235. Young EA CN, Brown MB. Twenty-four-hour ACTH and cortisol pulsatility in depressed women. Neuropsychopharmacology 2001;25(2):267-276.
236. Gold PW, Chrousos GP. Organization of the stress system and its dysregulation in melancholic and atypical depression: High vs low CRH/NE states. Mol Psychiatry 2002;7(3):254-275.
237. Miller LJ. Postpartum depression. JAMA 2002;287(6):762-765.
238. Taheri S, Gardiner J, Hafizi S, Murphy K, Dakin C, Seal L, Small C, Ghatei M, Bloom S. Orexin A immunoreactivity and preproorexin mRNA in the brain of Zucker and WKY rats. Neuroreport 2001;12(3):459-464.
239. Allard JS, Tizabi Y, Shaffery JP, Trouth CO, Manaye K. Stereological analysis of the hypothalamic hypocretin/orexin neurons in an animal model of depression. Neuropeptides 2004;38(5):311-315.
240. Ito N, Yabe T, Gamo Y, Nagai T, Oikawa T, Yamada H, Hanawa T. I.c.v. administration of orexin-A induces an antidepressive-like effect through hippocampal cell proliferation. Neuroscience 2008;157(4):720-732.
241. Vogel GW, Vogel F, McAbee RS, Thurmond AJ. Improvement of depression by REM sleep deprivation. New findings and a theory. Arch Gen Psychiatry 1980;37(3):247-253.
242. Allard JS, Tizabi Y, Shaffery JP, Manaye K. Effects of rapid eye movement sleep deprivation on hypocretin neurons in the hypothalamus of a rat model of depression. Neuropeptides 2007;41(5):329-337.
243. Lutter M, Krishnan V, Russo SJ, Jung S, McClung CA, Nestler EJ. Orexin signaling mediates the antidepressant-like effect of calorie restriction. J Neurosci 2008;28(12):3071-3075.
244. Mikrouli E, Wortwein G, Soylu R, Mathe AA, Petersen A. Increased numbers of orexin/hypocretin neurons in a genetic rat depression model. Neuropeptides 2011;45(6):401-406.
245. Scott MM, Marcus JN, Pettersen A, Birnbaum SG, Mochizuki T, Scammell TE, Nestler EJ, Elmquist JK, Lutter M. Hcrtr1 and 2 signaling differentially regulates depression-like behaviors. Behav Brain Res 2011;222(2):289-294.
246. Salomon RM, Ripley B, Kennedy JS, Johnson B, Schmidt D, Zeitzer JM, Nishino S, Mignot E. Diurnal variation of cerebrospinal fluid hypocretin-1 (Orexin-A) levels in control and depressed subjects. Biol Psychiatry 2003;54(2):96-104.
247. Brundin L, Bjorkqvist M, Petersen A, Traskman-Bendz L. Reduced orexin levels in the cerebrospinal fluid of suicidal patients with major depressive disorder. Eur Neuropsychopharmacol 2007;17(9):573-579.
248. Brundin L, Bjorkqvist M, Traskman-Bendz L, Petersen A. Increased orexin levels in the cerebrospinal fluid the first year after a suicide attempt. J Affect Disord 2009;113(1-2):179-182.
249. Brundin L, Petersen A, Bjorkqvist M, Traskman-Bendz L. Orexin and psychiatric symptoms in suicide attempters. J Affect Disord 2007;100(1-3):259-263.
250. Rotter A, Asemann R, Decker A, Kornhuber J, Biermann T. Orexin expression and promoter-methylation in peripheral blood of patients suffering from major depressive disorder. J Affect Disord 2011;131(1-3):186-192.
251. Suzuki M, Beuckmann CT, Shikata K, Ogura H, Sawai T. Orexin-A (hypocretin-1) is possibly involved in generation of anxiety-like behavior. Brain Res 2005;1044(1):116-121.
252. Li Y, Li S, Wei C, Wang H, Sui N, Kirouac GJ. Orexins in the paraventricular nucleus of the thalamus mediate anxiety-like responses in rats. Psychopharmacology (Berl) 2010;212(2):251-265.
253. Avolio E, Alo R, Carelli A, Canonaco M. Amygdalar orexinergic-GABAergic interactions regulate anxiety behaviors of the Syrian golden hamster. Behav Brain Res 2011;218(2):288-295.
254. Lungwitz EA, Molosh A, Johnson PL, Harvey BP, Dirks RC, Dietrich A, Minick P, Shekhar A, Truitt WA. Orexin-A induces anxiety-like behavior through interactions with glutamatergic receptors in the bed nucleus of the stria terminalis of rats. Physiol Behav 2012;107(5):726-732.
255. 2-mediated anxiety and hypertension but not bradycardia. Neuropsychopharmacology 2012;37(8):1911-1922.
256. Panhelainen AE, Korpi ER. Evidence for a role of inhibition of orexinergic neurons in the anxiolytic and sedative effects of diazepam: A c-Fos study. Pharmacol Biochem Behav 2012;101(1):115-124.
257. Singareddy R, Uhde T, Commissaris R. Differential effects of hypocretins on noise-alone versus potentiated startle responses. Physiol Behav 2006;89(5):650-655.
258. Rodgers RJ, Wright FL, Snow NF, Taylor LJ. Orexin-1 receptor antagonism fails to reduce anxiety-like behaviour in either plus-maze-naive or plus-maze-experienced mice. Behav Brain Res 2013;243:213-219.
259. Strawn JR, Pyne-Geithman GJ, Ekhator NN, Horn PS, Uhde TW, Shutter LA, Baker DG, Geracioti TD, Jr. Low cerebrospinal fluid and plasma orexin-A (hypocretin-1) concentrations in combat-related posttraumatic stress disorder. Psychoneuroendocrinology 2010;35(7):1001-1007.
260. Geracioti TD, Jr., Baker DG, Ekhator NN, West SA, Hill KK, Bruce AB, Schmidt D, Rounds-Kugler B, Yehuda R, Keck PE, Jr., Kasckow JW. CSF norepinephrine concentrations in posttraumatic stress disorder. Am J Psychiatry 2001;158(8):1227-1230.
261. Sears RM, Fink AE, Wigestrand MB, Farb CR, de Lecea L, Ledoux JE. Orexin/hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus. Proc Natl Acad Sci USA 2013;110(50):20260-20265.
262. Ponz A, Khatami R, Poryazova R, Werth E, Boesiger P, Schwartz S, Bassetti CL. Reduced amygdala activity during aversive conditioning in human narcolepsy. Ann Neurol 2010;67(3):394-398.
263. Poryazova R, Schnepf B, Werth E, Khatami R, Dydak U, Meier D, Boesiger P, Bassetti CL. Evidence for metabolic hypothalamo-amygdala dysfunction in narcolepsy. Sleep 2009;32(5):607-613.
264. van Os J, Kapur S. Schizophrenia. Lancet 2009;374(9690):635-645.
265. Moskvina V, Craddock N, Holmans P, Nikolov I, Pahwa JS, Green E, Owen MJ, O'Donovan MC. Gene-wide analyses of genome-wide association data sets: Evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk. Mol Psychiatry 2009;14(3):252-260.
266. Stefansson H, Rujescu D, Cichon S, Pietilainen OPH, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE, Hansen T, Jakobsen KD, Muglia P, Francks C, Matthews PM, Gylfason A, Halldorsson BV, Gudbjartsson D, Thorgeirsson TE, Sigurdsson A, Jonasdottir A, Jonasdottir A, Bjornsson A, Mattiasdottir S, Blondal T, Haraldsson M, Magnusdottir BB, Giegling I, Moller HJ, Hartmann A, Shianna KV, Ge DL, Need AC, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Paunio T, Toulopoulou T, Bramon E, Di Forti M, Murray R, Ruggeri M, Vassos E, Tosato S, Walshe M, Li T, Vasilescu C, Muhleisen TW, Wang AG, Ullum H, Djurovic S, Melle I, Olesen J, Kiemeney LA, Franke B, Sabatti C, Freimer NB, Gulcher JR, Thorsteinsdottir U, Kong A, Andreassen OA, Ophoff RA, Georgi A, Rietschel M, Werge T, Petursson H, Goldstein DB, Nothen MM, Peltonen L, Collier DA, St Clair D, Stefansson K. Large recurrent microdeletions associated with schizophrenia. Nature 2008;455(7210):232-261.
267. Cantor-Graae E, Selten JP. Schizophrenia and migration: A meta-analysis and review. Am J Psychiatry 2005;162(1):12-24.
268. Krabbendam L, van Os J. Schizophrenia and urbanicity: A major environmental influence - Conditional on genetic risk. Schizophr Bull 2005;31(4):795-799.
269. Brown AS. Prenatal infection as a risk factor for schizophrenia. Schizophr Bull 2006;32(2):200-202.
270. Kapur S, Mamo D. Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry 2003;27(7):1081-1090.
271. Guillin O, Abi-Dargham A, Laruelle M. Neurobiology of dopamine in schizophrenia. Int Rev Neurobiol 2007;78:1-39.
272. Nishino S, Ripley B, Mignot E, Benson KL, Zarcone VP. CSF hypocretin-1 levels in schizophrenics and controls: Relationship to sleep architecture. Psychiatry Res 2002;110(1):1-7.
273. Dalal MA, Schuld A, Pollmacher T. Lower CSF orexin A (hypocretin-1) levels in patients with schizophrenia treated with haloperidol compared to unmedicated subjects. Mol Psychiatry 2003;8(10):836-837.
274. Meerabux J, Iwayama Y, Sakurai T, Ohba H, Toyota T, Yamada K, Nagata R, Irukayama-Tomobe Y, Shimizu H, Yoshitsugu K, Ohta K, Yoshikawa T. Association of an orexin 1 receptor 408Val variant with polydipsia-hyponatremia in schizophrenic subjects. Biol Psychiatry 2005;58(5):401-407.
275. Fukunaka Y, Shinkai T, Hwang R, Hori H, Utsunomiya K, Sakata S, Naoe Y, Shimizu K, Matsumoto C, Ohmori O, Nakamura J. The orexin 1 receptor (HCRTR1) gene as a susceptibility gene contributing to polydipsia-hyponatremia in schizophrenia. Neuromolecular Med 2007;9(4):292-297.
276. Davie CA. A review of Parkinson's disease. Br Med Bull 2008;86:109-127.
277. Jankovic J. Parkinson's disease: Clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008;79(4):368-376.
278. Samii A, Nutt JG, Ransom BR. Parkinson's disease. Lancet 2004;363(9423):1783-1793.
279. Vendette M, Gagnon JF, Decary A, Massicotte-Marquez J, Postuma RB, Doyon J, Panisset M, Montplaisir J. REM sleep behavior disorder predicts cognitive impairment in Parkinson disease without dementia. Neurology 2007;69(19):1843-1849.
280. Dooneief G, Mirabello E, Bell K, Marder K, Stern Y, Mayeux R. An estimate of the incidence of depression in idiopathic Parkinson's disease. Arch Neurol 1992;49(3):305-307.
281. Drouot X, Moutereau S, Nguyen JP, Lefaucheur JP, Creange A, Remy P, Goldenberg F, d'Ortho MP. Low levels of ventricular CSF orexin/hypocretin in advanced PD. Neurology 2003;61(4):540-543.
282. Fronczek R, Overeem S, Lee SY, Hegeman IM, van Pelt J, van Duinen SG, Lammers GJ, Swaab DF. Hypocretin (orexin) loss in Parkinson's disease. Brain 2007;130(Pt 6):1577-1585.
283. Wienecke M, Werth E, Poryazova R, Baumann-Vogel H, Bassetti CL, Weller M, Waldvogel D, Storch A, Baumann CR. Progressive dopamine and hypocretin deficiencies in Parkinson's disease: Is there an impact on sleep and wakefulness? J Sleep Res 2012;21(6):710-717.
284. Maeda T, Nagata K, Kondo H, Kanbayashi T. Parkinson's disease comorbid with narcolepsy presenting low CSF hypocretin/orexin level. Sleep Med 2006;7(8):662.
285. Thannickal TC, Lai YY, Siegel JM. Hypocretin (orexin) cell loss in Parkinson's disease. Brain 2007;130(Pt 6):1586-1595.
286. Asai H, Hirano M, Furiya Y, Udaka F, Morikawa M, Kanbayashi T, Shimizu T, Ueno S. Cerebrospinal fluid-orexin levels and sleep attacks in four patients with Parkinson's disease. Clin Neurol Neurosurg 2009;111(4):341-344.
287. Overeem S, van Hilten JJ, Ripley B, Mignot E, Nishino S, Lammers GJ. Normal hypocretin-1 levels in Parkinson's disease patients with excessive daytime sleepiness. Neurology 2002;58(3):498-499.
288. Yasui K, Inoue Y, Kanbayashi T, Nomura T, Kusumi M, Nakashima K. CSF orexin levels of Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy and corticobasal degeneration. J Neurol Sci 2006;250(1-2):120-123.
289. Poceta JS, Parsons L, Engelland S, Kripke DF. Circadian rhythm of CSF monoamines and hypocretin-1 in restless legs syndrome and Parkinson's disease. Sleep Med 2009;10(1):129-133.
290. Baumann CR, Scammell TE, Bassetti CL. Parkinson's disease, sleepiness and hypocretin/orexin. Brain 2008;131(Pt 3):e91.
291. Compta Y, Santamaria J, Ratti L, Tolosa E, Iranzo A, Munoz E, Valldeoriola F, Casamitjana R, Rios J, Marti MJ. Cerebrospinal hypocretin, daytime sleepiness and sleep architecture in Parkinson's disease dementia. Brain 2009;132(Pt 12):3308-3317.
292. Drouot X, Moutereau S, Lefaucheur JP, Palfi S, Covali-Noroc A, Margarit L, Stoica-Herman M, Nguyen JP, Cesaro P, d'Ortho MP. Low level of ventricular CSF orexin-A is not associated with objective sleepiness in PD. Sleep Med 2011;12(9):936-937.
293. Baumann C, Ferini-Strambi L, Waldvogel D, Werth E, Bassetti CL. Parkinsonism with excessive daytime sleepiness-A narcolepsy-like disorder? J Neurol 2005;252(2):139-145.
294. Cui LB, Li BW, Jin XH, Zhao L, Shi J. Progressive changes of orexin system in a rat model of 6-hydroxydopamine-induced Parkinson's disease. Neurosci Bull 2010;26(5):381-387.
295. Michinaga S, Hisatsune A, Isohama Y, Katsuki H. An anti-Parkinson drug ropinirole depletes orexin from rat hypothalamic slice culture. Neurosci Res 2010;68(4):315-321.
296. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. Lancet 2011;377(9770):1019-1031.
297. Fronczek R, van Geest S, Frolich M, Overeem S, Roelandse FW, Lammers GJ, Swaab DF. Hypocretin (orexin) loss in Alzheimer's disease. Neurobiol Aging 2012;33(8):1642-1650.
298. Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 2009;326(5955):1005-1007.
299. Scammell TE, Matheson JK, Honda M, Thannickal TC, Siegel JM. Coexistence of narcolepsy and Alzheimer's disease. Neurobiol Aging 2012;33(7):1318-1319.
300. Wennstrom M, Londos E, Minthon L, Nielsen HM. Altered CSF orexin and alpha-synuclein levels in dementia patients. J Alzheimers Dis 2012;29(1):125-132.
301. Lessig S, Ubhi K, Galasko D, Adame A, Pham E, Remidios K, Chang M, Hansen LA, Masliah E. Reduced hypocretin (orexin) levels in dementia with Lewy bodies. Neuroreport 2010;21(11):756-760.
302. Friedman LF, Zeitzer JM, Lin L, Hoff D, Mignot E, Peskind ER, Yesavage JA. In Alzheimer disease, increased wake fragmentation found in those with lower hypocretin-1. Neurology 2007;68(10):793-794.
303. Schmidt FM, Kratzsch J, Gertz HJ, Tittmann M, Jahn I, Pietsch UC, Kaisers UX, Thiery J, Hegerl U, Schoknecht P. Cerebrospinal fluid melanin-concentrating hormone (MCH) and hypocretin-1 (HCRT-1, orexin-A) in Alzheimer's disease. PLoS One 2013;8(5):e63136.
304. Walker FO. Huntington's disease. Lancet 2007;369(9557):218-228.
305. Phillips W, Shannon KM, Barker RA. The current clinical management of Huntington's disease. Mov Disord 2008;23(11):1491-1504.
306. Aziz NA, Anguelova GV, Marinus J, Lammers GJ, Roos RA. Sleep and circadian rhythm alterations correlate with depression and cognitive impairment in Huntington's disease. Parkinsonism Relat Disord 2010;16(5):345-350.
307. Duff K, Paulsen JS, Beglinger LJ, Langbehn DR, Stout JC. Psychiatric symptoms in Huntington's disease before diagnosis: The predict-HD study. Biol Psychiatry 2007;62(12):1341-1346.
308. Roos RA, Aziz NA. Hypocretin-1 and secondary signs in Huntington's disease. Parkinsonism Relat Disord 2007;13 Suppl 3:S387-390.
309. Aziz A, Fronczek R, Maat-Schieman M, Unmehopa U, Roelandse F, Overeem S, van Duinen S, Lammers GJ, Swaab D, Roos R. Hypocretin and melanin-concentrating hormone in patients with Huntington disease. Brain Pathol 2008;18(4):474-483.
310. Gabery S, Murphy K, Schultz K, Loy CT, McCusker E, Kirik D, Halliday G, Petersen A. Changes in key hypothalamic neuropeptide populations in Huntington disease revealed by neuropathological analyses. Acta Neuropathol 2010;120(6):777-788.
311. Meier A, Mollenhauer B, Cohrs S, Rodenbeck A, Jordan W, Meller J, Otto M. Normal hypocretin-1 (orexin-A) levels in the cerebrospinal fluid of patients with Huntington's disease. Brain Res 2005;1063(2):201-203.
312. Gaus SE, Lin L, Mignot E. CSF hypocretin levels are normal in Huntington's disease patients. Sleep 2005;28(12):1607-1608.
313. Baumann CR, Hersberger M, Bassetti CL. Hypocretin-1 (orexin A) levels are normal in Huntington's disease. J Neurol 2006;253(9):1232-1233.
314. Hult Lundh S, Nilsson N, Soylu R, Kirik D, Petersen A. Hypothalamic expression of mutant huntingtin contributes to the development of depressive-like behavior in the BAC transgenic mouse model of Huntington's disease. Hum Mol Genet 2013;22(17):3485-3497.
315. Petersen A, Gil J, Maat-Schieman ML, Bjorkqvist M, Tanila H, Araujo IM, Smith R, Popovic N, Wierup N, Norlen P, Li JY, Roos RA, Sundler F, Mulder H, Brundin P. Orexin loss in Huntington's disease. Hum Mol Genet 2005;14(1):39-47.
316. Williams RH, Morton AJ, Burdakov D. Paradoxical function of orexin/hypocretin circuits in a mouse model of Huntington's disease. Neurobiol Dis 2011;42(3):438-445.
317. Wulff K, Gatti S, Wettstein JG, Foster RG. Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease. Nat Rev Neurosci 2010;11(8):589-599.
318. Pigeon WR, Hegel M, Unutzer J, Fan MY, Sateia MJ, Lyness JM, Phillips C, Perlis ML. Is insomnia a perpetuating factor for late-life depression in the IMPACT cohort? Sleep 2008;31(4):481-488.
319. Kessler RC DR, Berglund P, Wittchen HU. Impairment in pure and comorbid generalized anxiety disorder and major depression at 12 months in two national surveys. Am J Psychiatry 1999;156:1915-1923.
320. Swendsen J, Conway KP, Degenhardt L, Glantz M, Jin R, Merikangas KR, Sampson N, Kessler RC. Mental disorders as risk factors for substance use, abuse and dependence: Results from the 10-year follow-up of the National Comorbidity Survey. Addiction 2010;105(6):1117-1128.
321. John J, Wu MF, Siegel JM. Systemic administration of hypocretin-1 reduces cataplexy and normalizes sleep and waking durations in narcoleptic dogs. Sleep Res Online 2000;3(1):23-28.
322. Mieda M, Willie JT, Hara J, Sinton CM, Sakurai T, Yanagisawa M. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci USA 2004;101(13):4649-4654.
323. Fujiki N, Yoshida Y, Ripley B, Mignot E, Nishino S. Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog. Sleep 2003;26(8):953-959.
324. Kastin AJ, Pan W, Maness LM, Banks WA. Peptides crossing the blood-brain barrier: Some unusual observations. Brain Res 1999;848(1-2):96-100.
325. Baier PC, Hallschmid M, Seeck-Hirschner M, Weinhold SL, Burkert S, Diessner N, Goder R, Aldenhoff JB, Hinze-Selch D. Effects of intranasal hypocretin-1 (orexin A) on sleep in narcolepsy with cataplexy. Sleep Med 2011;12(10):941-946.
326. Baier PC, Weinhold SL, Huth V, Gottwald B, Ferstl R, Hinze-Selch D. Olfactory dysfunction in patients with narcolepsy with cataplexy is restored by intranasal Orexin A (Hypocretin-1). Brain 2008;131(Pt 10):2734-2741.
327. Porter RA, Chan WN, Coulton S, Johns A, Hadley MS, Widdowson K, Jerman JC, Brough SJ, Coldwell M, Smart D, Jewitt F, Jeffrey P, Austin N. 1, 3-Biarylureas as selective non-peptide antagonists of the orexin-1 receptor. Bioorg Med Chem Lett 2001;11(14):1907-1910.
328. Smart D, Sabido-David C, Brough SJ, Jewitt F, Johns A, Porter RA, Jerman JC. SB-334867-A: The first selective orexin-1 receptor antagonist. Br J Pharmacol 2001;132(6):1179-1182.
329. Putula J, Kukkonen JP. Mapping of the binding sites for the OX1 orexin receptor antagonist, SB-334867, using orexin/hypocretin receptor chimaeras. Neurosci Lett 2012;506(1):111-115.
330. Perrey DA, Gilmour BP, Runyon SP, Thomas BF, Zhang Y. Diaryl urea analogues of SB-334867 as orexin-1 receptor antagonists. Bioorg Med Chem Lett 2011;21(10):2980-2985.
331. Langmead CJ, Jerman JC, Brough SJ, Scott C, Porter RA, Herdon HJ. Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor. Br J Pharmacol 2004;141(2):340-346.
332. Asahi S, Egashira S, Matsuda M, Iwaasa H, Kanatani A, Ohkubo M, Ihara M, Morishima H. Development of an orexin-2 receptor selective agonist, [Ala(11), D-Leu(15)]orexin-B. Bioorg Med Chem Lett 2003;13(1):111-113.
333. Hirose M, Egashira S, Goto Y, Hashihayata T, Ohtake N, Iwaasa H, Hata M, Fukami T, Kanatani A, Yamada K. N-acyl 6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline: The first orexin-2 receptor selective non-peptidic antagonist. Bioorg Med Chem Lett 2003;13(24):4497-4499.
334. McAtee LC, Sutton SW, Rudolph DA, Li X, Aluisio LE, Phuong VK, Dvorak CA, Lovenberg TW, Carruthers NI, Jones TK. Novel substituted 4-phenyl-[1, 3]dioxanes: Potent and selective orexin receptor 2 (OX(2)R) antagonists. Bioorg Med Chem Lett 2004;14(16):4225-4229.
335. Cole AG, Stroke IL, Qin LY, Hussain Z, Simhadri S, Brescia MR, Waksmunski FS, Strohl B, Tellew JE, Williams JP, Saunders J, Appell KC, Henderson I, Webb ML. Synthesis of (3, 4-dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists. Bioorg Med Chem Lett 2008;18(20):5420-5423.
336. Malherbe P, Borroni E, Gobbi L, Knust H, Nettekoven M, Pinard E, Roche O, Rogers-Evans M, Wettstein JG, Moreau JL. Biochemical and behavioural characterization of EMPA, a novel high-affinity, selective antagonist for the OX(2) receptor. Br J Pharmacol 2009;156(8):1326-1341.
337. Micheli F, Antolini M, Di Fabio R, Pellacani A, Pozzan A. 2-Methyl-3-furanyl-4H-1, 2, 4-triazol-3-ylthioamides: A new class of selective orexin 2 antagonists. Bioorg Med Chem Lett 2010;20(22):6405-6407.
338. Fujimoto T, Kunitomo J, Tomata Y, Nishiyama K, Nakashima M, Hirozane M, Yoshikubo S, Hirai K, Marui S. Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists. Bioorg Med Chem Lett 2011;21(21):6414-6416.
339. Fujimoto T, Tomata Y, Kunitomo J, Hirozane M, Marui S. Discovery of spiropiperidine-based potent and selective Orexin-2 receptor antagonists. Bioorg Med Chem Lett 2011;21(21):6409-6413.
340. Mercer SP, Roecker AJ, Garson S, Reiss DR, Harrell CM, Murphy KL, Bruno JG, Bednar RA, Lemaire W, Cui DH, Cabalu TD, Tang CY, Prueksaritanont T, Hartman GD, Young SD, Winrow CJ, Renger JJ, Coleman PJ. Discovery of 2, 5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs). Bioorg Med Chem Lett 2013;23(24):6620-6624.
341. Kummangal BA, Kumar D, Mallick HN. Intracerebroventricular injection of orexin-2 receptor antagonist promotes REM sleep. Behav Brain Res 2013;237:59-62.
342. Malherbe P, Borroni E, Pinard E, Wettstein JG, Knoflach F. Biochemical and electrophysiological characterization of almorexant, a dual orexin 1 receptor (OX1)/orexin 2 receptor (OX2) antagonist: Comparison with selective OX1 and OX2 antagonists. Mol Pharmacol 2009;76(3):618-631.
343. Mang GM, Durst T, Burki H, Imobersteg S, Abramowski D, Schuepbach E, Hoyer D, Fendt M, Gee CE. The dual orexin receptor antagonist almorexant induces sleep and decreases orexin-induced locomotion by blocking orexin 2 receptors. Sleep 2012;35(12):1625-1635.
344. Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S, Mueller C, Nayler O, van Gerven J, de Haas SL, Hess P, Qiu C, Buchmann S, Scherz M, Weller T, Fischli W, Clozel M, Jenck F. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 2007;13(2):150-155.
345. Hoever P, de Haas SL, Dorffner G, Chiossi E, van Gerven JM, Dingemanse J. Orexin receptor antagonism: An ascending multiple-dose study with almorexant. J Psychopharmacol 2012;26(8):1071-1080.
346. Hoever P, Dorffner G, Benes H, Penzel T, Danker-Hopfe H, Barbanoj MJ, Pillar G, Saletu B, Polo O, Kunz D, Zeitlhofer J, Berg S, Partinen M, Bassetti CL, Hogl B, Ebrahim IO, Holsboer-Trachsler E, Bengtsson H, Peker Y, Hemmeter UM, Chiossi E, Hajak G, Dingemanse J. Orexin receptor antagonism, a new sleep-enabling paradigm: A proof-of-concept clinical trial. Clin Pharmacol Ther 2012;91(6):975-985.
347. Bettica P, Nucci G, Pyke C, Squassante L, Zamuner S, Ratti E, Gomeni R, Alexander R. Phase I studies on the safety, tolerability, pharmacokinetics and pharmacodynamics of SB-649868, a novel dual orexin receptor antagonist. J Psychopharmacol 2012;26(8):1058-1070.
348. Bettica P, Squassante L, Groeger JA, Gennery B, Winsky-Sommerer R, Dijk DJ. Differential effects of a dual orexin receptor antagonist (SB-649868) and zolpidem on sleep initiation and consolidation, SWS, REM sleep, and EEG power spectra in a model of situational insomnia. Neuropsychopharmacology 2012;37(5):1224-1233.
349. Bettica P, Squassante L, Zamuner S, Nucci G, Danker-Hopfe H, Ratti E. The orexin antagonist SB-649868 promotes and maintains sleep in men with primary insomnia. Sleep 2012;35(8):1097-1104.
350. Cox CD, Breslin MJ, Whitman DB, Schreier JD, McGaughey GB, Bogusky MJ, Roecker AJ, Mercer SP, Bednar RA, Lemaire W, Bruno JG, Reiss DR, Harrell CM, Murphy KL, Garson SL, Doran SM, Prueksaritanont T, Anderson WB, Tang C, Roller S, Cabalu TD, Cui D, Hartman GD, Young SD, Koblan KS, Winrow CJ, Renger JJ, Coleman PJ. Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1, 3-benzoxazol-2-yl)-7-methyl-1, 4-diazepan-1-yl][5-methyl-2-(2H -1, 2, 3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. J Med Chem 2010;53(14):5320-5332.
351. Winrow CJ, Gotter AL, Cox CD, Doran SM, Tannenbaum PL, Breslin MJ, Garson SL, Fox SV, Harrell CM, Stevens J, Reiss DR, Cui D, Coleman PJ, Renger JJ. Promotion of sleep by suvorexant-A novel dual orexin receptor antagonist. J Neurogenet 2011;25(1-2):52-61.
352. Betschart C, Hintermann S, Behnke D, Cotesta S, Fendt M, Gee CE, Jacobson LH, Laue G, Ofner S, Chaudhari V, Badiger S, Pandit C, Wagner J, Hoyer D. Identification of a novel series of orexin receptor antagonists with a distinct effect on sleep architecture for the treatment of insomnia. J Med Chem 2013;56(19):7590-7607.
353. Hoyer D, Durst T, Fendt M, Jacobson LH, Betschart C, Hintermann S, Behnke D, Cotesta S, Laue G, Ofner S, Legangneux E, Gee CE. Distinct effects of IPSU and suvorexant on mouse sleep architecture. Front Neurosci 2013;7:235.
354. Sun H, Kennedy WP, Wilbraham D, Lewis N, Calder N, Li X, Ma J, Yee KL, Ermlich S, Mangin E, Lines C, Rosen L, Chodakewitz J, Murphy GM. Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men. Sleep 2013;36(2):259-267.
355. Herring WJ, Snyder E, Budd K, Hutzelmann J, Snavely D, Liu K, Lines C, Roth T, Michelson D. Orexin receptor antagonism for treatment of insomnia: A randomized clinical trial of suvorexant. Neurology 2012;79(23):2265-2274.
356. Michelson D, Snyder E, Paradis E, Chengan-Liu M, Snavely DB, Hutzelmann J, Walsh JK, Krystal AD, Benca RM, Cohn M, Lines C, Roth T, Herring WJ. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: A phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014;13(5):461-471.
357. Coleman PJ, Schreier JD, Cox CD, Breslin MJ, Whitman DB, Bogusky MJ, McGaughey GB, Bednar RA, Lemaire W, Doran SM, Fox SV, Garson SL, Gotter AL, Harrell CM, Reiss DR, Cabalu TD, Cui D, Prueksaritanont T, Stevens J, Tannenbaum PL, Ball RG, Stellabott J, Young SD, Hartman GD, Winrow CJ, Renger JJ. Discovery of [(2R, 5R)-5-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl][5-methyl-2 -(pyrimidin-2-yl)phenyl]methanone (MK-6096): A dual orexin receptor antagonist with potent sleep-promoting properties. ChemMedChem 2012;7(3):415-424, 337.
358. Winrow CJ, Gotter AL, Cox CD, Tannenbaum PL, Garson SL, Doran SM, Breslin MJ, Schreier JD, Fox SV, Harrell CM, Stevens J, Reiss DR, Cui D, Coleman PJ, Renger JJ. Pharmacological characterization of MK-6096 - A dual orexin receptor antagonist for insomnia. Neuropharmacology 2012;62(2):978-987.
359. Moorman DE, Aston-Jones G. Orexin-1 receptor antagonism decreases ethanol consumption and preference selectively in high-ethanol-preferring Sprague-Dawley rats. Alcohol 2009;43(5):379-386.
360. LeSage MG, Perry JL, Kotz CM, Shelley D, Corrigall WA. Nicotine self-administration in the rat: Effects of hypocretin antagonists and changes in hypocretin mRNA. Psychopharmacology (Berl) 2010;209(2):203-212.
361. Plaza-Zabala A, Flores A, Maldonado R, Berrendero F. Hypocretin/orexin signaling in the hypothalamic paraventricular nucleus is essential for the expression of nicotine withdrawal. Biol Psychiatry 2012;71(3):214-223.
362. Piccoli L, Micioni Di Bonaventura MV, Cifani C, Costantini VJ, Massagrande M, Montanari D, Martinelli P, Antolini M, Ciccocioppo R, Massi M, Merlo-Pich E, Di Fabio R, Corsi M. Role of orexin-1 receptor mechanisms on compulsive food consumption in a model of binge eating in female rats. Neuropsychopharmacology 2012;37(9):1999-2011.
363. Chen X, Wang H, Lin Z, Li S, Li Y, Bergen HT, Vrontakis ME, Kirouac GJ. Orexins (hypocretins) contribute to fear and avoidance in rats exposed to a single episode of footshocks. Brain Struct Funct 2013.
364. Nollet M, Gaillard P, Tanti A, Girault V, Belzung C, Leman S. Neurogenesis-independent antidepressant-like effects on behavior and stress axis response of a dual orexin receptor antagonist in a rodent model of depression. Neuropsychopharmacology 2012;37(10):2210-2221.
365. Johren O, Neidert SJ, Kummer M, Dendorfer A, Dominiak P. Prepro-orexin and orexin receptor mRNAs are differentially expressed in peripheral tissues of male and female rats. Endocrinology 2001;142(8):3324-3331.
366. Kastin AJ, Akerstrom V. Orexin A but not orexin B rapidly enters brain from blood by simple diffusion. J Pharmacol Exp Ther 1999;289(1):219-223.
367. Liu M, Blanco-Centurion C, Konadhode R, Begum S, Pelluru D, Gerashchenko D, Sakurai T, Yanagisawa M, van den Pol AN, Shiromani PJ. Orexin gene transfer into zona incerta neurons suppresses muscle paralysis in narcoleptic mice. J Neurosci 2011;31(16):6028-6040.
368. Kantor S, Mochizuki T, Lops SN, Ko B, Clain E, Clark E, Yamamoto M, Scammell TE. Orexin gene therapy restores the timing and maintenance of wakefulness in narcoleptic mice. Sleep 2013;36(8):1129-1138.
369. Blanco-Centurion C, Liu M, Konadhode R, Pelluru D, Shiromani PJ. Effects of orexin gene transfer in the dorsolateral pons in orexin knockout mice. Sleep 2013;36(1):31-40.
370. Mochizuki T, Arrigoni E, Marcus JN, Clark EL, Yamamoto M, Honer M, Borroni E, Lowell BB, Elmquist JK, Scammell TE. Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice. Proc Natl Acad Sci USA 2011;108(11):4471-4476.
371. Arias-Carrion O, Murillo-Rodriguez E, Xu M, Blanco-Centurion C, Drucker-Colin R, Shiromani PJ. Transplantation of hypocretin neurons into the pontine reticular formation: Preliminary results. Sleep 2004;27(8):1465-1470.
372. Arias-Carrion O, Murillo-Rodriguez E. Effects of hypocretin/orexin cell transplantation on narcoleptic-like sleep behavior in rats. PLoS One 2014;9(4):e95342.
373. Blouin AM, Fried I, Wilson CL, Staba RJ, Behnke EJ, Lam HA, Maidment NT, Karlsson KAE, Lapierre JL, Siegel JM. Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction. Nat Commun 2013;4:1547.
374. Tye KM, Prakash R, Kim SY, Fenno LE, Grosenick L, Zarabi H, Thompson KR, Gradinaru V, Ramakrishnan C, Deisseroth K. Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 2011;471(7338):358-362.
375. Carter ME, Brill J, Bonnavion P, Huguenard JR, Huerta R, de Lecea L. Mechanism for Hypocretin-mediated sleep-to-wake transitions. Proc Natl Acad Sci USA 2012;109(39):E2635-E2644.